FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature

Sabine, Amélie; Bovay, Esther; Demir, Cansaran Saygili; Kimura, Wataru; Jaquet, Muriel; Agalarov, Yan; Zangger, Nadine; Scallan, Joshua P; Graber, Werner Adrian; Gulpinar, Elgin; Kwak, Brenda R; Mäkinen, Taija; Martinez-Corral, Inés; Ortega, Sagrario; Delorenzi, Mauro; Kiefer, Friedemann; Davis, Michael J; Djonov, Valentin; Miura, Naoyuki and Petrova, Tatiana V (2015). FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature. Journal of clinical investigation, 125(10), pp. 3861-3877. American Society for Clinical Investigation 10.1172/JCI80454

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Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Topographical and Clinical Anatomy

UniBE Contributor:

Graber, Werner Adrian and Djonov, Valentin

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0021-9738

Publisher:

American Society for Clinical Investigation

Language:

English

Submitter:

Ruslan Hlushchuk

Date Deposited:

08 Mar 2016 14:54

Last Modified:

08 Mar 2016 14:54

Publisher DOI:

10.1172/JCI80454

PubMed ID:

26389677

BORIS DOI:

10.7892/boris.76430

URI:

https://boris.unibe.ch/id/eprint/76430

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